Janey Prodoehl

High-resolution diffusion tensor imaging in the substantia nigra of de novo Parkinson disease

Background: In the midbrain of patients with Parkinson disease (PD), there is a selective loss of dopaminergic neurons in the ventrolateral and caudal substantia nigra (SN). In a mouse model of PD, investigators have administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and found that measures derived using diffusion tensor imaging (DTI) were correlated with the number of dopamine neurons lost following intoxication. Methods: Twenty-eight subjects (14 with early stage, untreated PD and 14 age- and gender-matched controls) were studied with a high-resolution DTI protocol at 3 Tesla using an eight-channel phase array coil and parallel imaging to study specific segments of degeneration in the SN. Regions of interest were drawn in the rostral, middle, and caudal SN by two blinded and independent raters. Results: Fractional anisotropy (FA) was reduced in the SN of subjects with PD compared with controls (p < 0.001). Post hoc analysis identified that reduced FA for patients with PD was greater in the caudal compared with the rostral region of interest (p < 0.00001). A receiver operator characteristic analysis in the caudal SN revealed that sensitivity and specificity were 100% for distinguishing patients with PD from healthy subjects. Findings were consistent across both raters. Conclusions: These findings provide evidence that high resolution diffusion tensor imaging in the substantia nigra distinguishes early stage, de novo patients with Parkinson disease (PD) from healthy individuals on a patient by patient basis and has the potential to serve as a noninvasive early biomarker for PD.

Basal ganglia mechanisms underlying precision grip force control.

The classic grasping network has been well studied but thus far the focus has been on cortical regions in the control of grasping. Sub-cortically, specific nuclei of the basal ganglia have been shown to be important in different aspects of precision grip force control but these findings have not been well integrated. In this review, we outline the evidence to support the hypothesis that key basal ganglia nuclei are involved in parameterizing specific properties of precision grip force. We review literature from different areas of human and animal work that converges to build a case for basal ganglia involvement in the control of precision gripping. Following on from literature showing anatomical connectivity between the basal ganglia nuclei and key nodes in the cortical grasping network, we suggest a conceptual framework for how the basal ganglia could function within the grasping network, particularly as it relates to the control of precision grip force.

Diffusion Tensor Imaging of Parkinson's Disease, Atypical Parkinsonism, and Essential Tremor

Diffusion tensor imaging could be useful in characterizing movement disorders because it noninvasively examines multiple brain regions simultaneously. We report a multitarget imaging approach focused on the basal ganglia and cerebellum in Parkinsons disease, parkinsonian variant of multiple system atrophy, progressive supranuclear palsy, and essential tremor and in healthy controls. Seventy‐two subjects were studied with a diffusion tensor imaging protocol at 3 Tesla. Receiver operating characteristic analysis was performed to directly compare groups. Sensitivity and specificity values were quantified for control versus movement disorder (92% sensitivity, 88% specificity), control versus parkinsonism (93% sensitivity, 91% specificity), Parkinsons disease versus atypical parkinsonism (90% sensitivity, 100% specificity), Parkinsons disease versus multiple system atrophy (94% sensitivity, 100% specificity), Parkinsons disease versus progressive supranuclear palsy (87% sensitivity, 100% specificity), multiple system atrophy versus progressive supranuclear palsy (90% sensitivity, 100% specificity), and Parkinsons disease versus essential tremor (92% sensitivity, 87% specificity). The brain targets varied for each comparison, but the substantia nigra, putamen, caudate, and middle cerebellar peduncle were the most frequently selected brain regions across classifications. These results indicate that using diffusion tensor imaging of the basal ganglia and cerebellum accurately classifies subjects diagnosed with Parkinsons disease, atypical parkinsonism, and essential tremor and clearly distinguishes them from control subjects.

Basal ganglia hypoactivity during grip force in drug naïve Parkinson's disease

The basal ganglia (BG) are impaired in Parkinsons disease (PD), but it remains unclear which nuclei are impaired during the performance of motor tasks in early‐stage PD. Therefore, this study was conducted to determine which nuclei function abnormally, and whether cortical structures are also affected by early‐stage PD. The study also determined if cerebellar hyperactivity is found early in the course of PD. Blood oxygenation level dependent activation was compared between 14 early‐stage drug‐naïve PD patients and 14 controls performing two precision grip force tasks using functional magnetic resonance imaging at 3 T. The grip tasks used in this study were chosen because both tasks are known to provide robust activation in BG nuclei, and the two tasks were similar except that the 2‐s task required more switching between contraction and relaxation than the 4‐s task. The 4‐s task revealed that PD patients were hypoactive relative to controls only in putamen and external globus pallidus, and thalamus. In the 2‐s task, PD patients were hypoactive throughout all BG nuclei, thalamus, M1, and supplementary motor area. There were no differences in cerebellar activation between groups during either task. Regions of interest analysis revealed that the hypoactivity observed in PD patients during the 2‐s task became more pronounced over time as patients performed the task. This suggests that a motor task that requires switching can accentuate abnormal activity throughout all BG nuclei of early‐stage, drug‐naive PD, and that the abnormal activity becomes more pronounced with repeated task performance in these patients. Hum Brain Mapp, 2010.

Differences in Brain Activation Between Tremor- and Nontremor-Dominant Parkinson Disease

OBJECTIVE To compare differences in functional brain activity between tremor- and nontremor-dominant subtypes of Parkinson disease (PD) using functional magnetic resonance imaging. DESIGN In our study, patients with tremor-dominant PD and those with nontremor-dominant PD performed a grip task, and the results obtained were compared using voxelwise analysis. Areas of the brain that were significantly different were then examined using a region-of-interest analysis to compare these patients with healthy controls. Voxel-based morphometry was used to determine macroscopic differences in gray and white matter volume between patient groups. SETTING University-affiliated research institution. PARTICIPANTS A total of 20 drug-naive patients with PD (10 with tremor-dominant PD and 10 with nontremor-dominant PD) and a total of 20 healthy controls. MAIN OUTCOME MEASURES Blood oxygenation level-dependent activation and percent signal change. RESULTS Robust findings across both voxelwise and region-of-interest analyses showed that, compared with patients with tremor-dominant PD, patients with nontremor-dominant PD had reduced activation in the ipsilateral dorsolateral prefrontal cortex, the globus pallidus interna, and the globus pallidus externa. Region-of-interest analyses confirmed that patients with nontremor-dominant PD had reduced activity in the ipsilateral dorsolateral prefrontal cortex, the globus pallidus interna, and the globus pallidus externa compared with patients with tremor-dominant PD and healthy controls. Patients with tremor-dominant PD had increased activity in the contralateral dorsolateral prefrontal cortex compared with patients with nontremor-dominant PD and healthy controls. These results could not be explained by differences in gray or white matter volume. CONCLUSIONS Reduced brain activity occurs in the prefrontal cortex and globus pallidus of patients with nontremor-dominant PD compared with both patients with tremor-dominant PD and healthy controls, which suggests that functional magnetic resonance imaging is a promising technique to understand differences in brain activation between subtypes of PD.

Blood Oxygenation Level Dependent Activation in Basal Ganglia Nuclei Relates to Specific Symptoms in De Novo Parkinson's Disease

To aid the development of symptomatic and disease modifying therapies in Parkinsons disease (PD), there is a strong need to identify noninvasive measures of basal ganglia (BG) function that are sensitive to disease severity. This study examines the relation between blood oxygenation level–dependent (BOLD) activation in every nucleus of the BG and symptom‐specific disease severity in early stage de novo PD. BOLD activation measured at 3 T was compared between 20 early stage de novo PD patients and 20 controls during an established precision grip force task. In addition to the BG nuclei, activation in specific thalamic and cortical regions was examined. There were three novel findings. First, there were significant negative correlations between total motor Unified PD Rating Scale and BOLD activation in bilateral caudate, bilateral putamen, contralateral external segment of the globus pallidus, bilateral subthalamic nucleus, contralateral substantia nigra, and thalamus. Second, bradykinesia was the symptom that most consistently predicted BOLD activation in the BG and thalamus. Also, BOLD activation in the contralateral internal globus pallidus was related to tremor. Third, the reduced cortical activity in primary motor cortex and supplementary motor area in de novo PD did not relate to motor symptoms. These findings demonstrate that BOLD activity in nuclei of the BG relates most consistently to bradykinesia and functional magnetic resonance imaging has strong potential to serve as a noninvasive marker for the state of BG function in de novo PD.

Effects of aging on the ventral and dorsal substantia nigra using diffusion tensor imaging

Dopaminergic neurons in the substantia nigra produce dopamine for the nigrostriatal pathway that facilitates motor function. Postmortem examinations demonstrate an age-related loss of cells in the substantia nigra, with most of the cell loss focused on the dorsal substantia nigra compared with the ventral substantia nigra. The current study used diffusion tensor imaging (DTI) to provide the first in vivo assessment of age-related degeneration in specific segments of the substantia nigra of humans. Measures extracted from DTI of 16 young adults (19-27 years) and 15 older adults (55-71 years) showed that in the dorsal substantia nigra, fractional anisotropy was reduced and radial diffusivity was increased with age. In the ventral substantia nigra and red nucleus, there were no differences across age for the DTI measures. DTI provides a noninvasive technique that accurately reflects the established pattern of age-related cell loss in the dorsal and ventral substantia nigra, further suggesting the robust potential for using DTI to characterize degeneration in the nigrostriatal pathway in both health and disease.

Two-year exercise program improves physical function in Parkinson's disease: the PRET-PD randomized clinical trial.

Background. The progressive resistance exercise (PRE) in Parkinson’s disease trial (PRET-PD) showed that PRE improved the motor signs of PD compared to a modified Fitness Counts (mFC) program. It is unclear how long-term exercise affects physical function in these individuals. Objective. To examine the effects of long-term PRE and mFC on physical function outcome measures in individuals with PD. Methods. A preplanned secondary analysis was conducted using data from the 38 patients with idiopathic PD who completed the PRET-PD trial. Participants were randomized into PRE or mFC groups and exercised 2 days/week up to 24 months. Blinded assessors obtained functional outcomes on and off medication at baseline, 6 and 24 months with the Modified Physical Performance Test, 5 times sit to stand test, Functional Reach Test, Timed Up and Go, Berg Balance Scale, 6 minute walk test (6MWT), and 50-ft walking speed (walk speed). Results. The groups did not differ on any physical function measure at 6 or 24 months (Ps > .1). Across time, all physical function measures improved from baseline to 24 months when tested on medication (Ps < .0001), except for 6MWT (P = .068). Off medication results were similar except that the 6MWT was now significant. Conclusions. Twenty-four months of supervised and structured exercise (either PRE or mFC) is effective at improving functional performance outcomes in individuals with moderate PD. Clinicians should strive to include structured and supervised exercise in the long-term plan of care for individuals with PD.

Progressive Resistance Exercise and Parkinson's Disease: A Review of Potential Mechanisms

This paper reviews the therapeutically beneficial effects of progressive resistance exercise (PRE) on Parkinsons disease (PD). First, this paper discusses the rationale for PRE in PD. Within the first section, the review discusses the central mechanisms that underlie bradykinesia and muscle weakness, highlights findings related to the central changes that accompany PRE in healthy individuals, and extends these findings to individuals with PD. It then illustrates the hypothesized positive effects of PRE on nigro-striatal-thalamo-cortical activation and connectivity. Second, it reviews recent findings of the use of PRE in individuals with PD. Finally, knowledge gaps of using PRE on individuals with PD are discussed along with suggestions for future research.

Two-Year Exercise Program Improves Physical Function in Parkinson’s Disease

Background. The progressive resistance exercise (PRE) in Parkinson’s disease trial (PRET-PD) showed that PRE improved the motor signs of PD compared to a modified Fitness Counts (mFC) program. It is unclear how long-term exercise affects physical function in these individuals. Objective. To examine the effects of long-term PRE and mFC on physical function outcome measures in individuals with PD. Methods. A preplanned secondary analysis was conducted using data from the 38 patients with idiopathic PD who completed the PRET-PD trial. Participants were randomized into PRE or mFC groups and exercised 2 days/week up to 24 months. Blinded assessors obtained functional outcomes on and off medication at baseline, 6 and 24 months with the Modified Physical Performance Test, 5 times sit to stand test, Functional Reach Test, Timed Up and Go, Berg Balance Scale, 6 minute walk test (6MWT), and 50-ft walking speed (walk speed). Results. The groups did not differ on any physical function measure at 6 or 24 months (Ps > .1). Across time, all physical function measures improved from baseline to 24 months when tested on medication (Ps < .0001), except for 6MWT (P = .068). Off medication results were similar except that the 6MWT was now significant. Conclusions. Twenty-four months of supervised and structured exercise (either PRE or mFC) is effective at improving functional performance outcomes in individuals with moderate PD. Clinicians should strive to include structured and supervised exercise in the long-term plan of care for individuals with PD.